dose escalation and expansion study of syh2043 in patients with advanced malignant tumors

Conditions: Advanced Malignant Tumors

Summary: the aim of this study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of syh2043 in patients with advanced malignant tumors.

this study is an open-label, single-arm, multi-center phase i clinical study, which includes four stages: a: dose-escalation stage: the dose escalation stage is divided into 5 dose levels, and a bayesian optimal interval design (boin) including accelerated titration will be used for dose escalation. b: pk expansion stage: two or three dose groups will be selected for pk expansion; after pk extension the cohort extension study will be conducted as required, and will include 4 cohorts according to the tumor types. c: combination dose escalation: this study will use a 3+3 design with up to 2 dose escalation cohorts at increasing levels. d: according to the results of stage c, 1-2 combination doses will be selected for combination dose expansion, and simon 2 stage was adopted for the expansion stage.

Eligibility criteria:
inclusion criteria: * 1. patients aged 18-75 years (inclusive); * 2. histological or cytological confirmation of advanced malignant tumors; * 3. patients who failed or were intolerant to standard treatment or had no standard treatment, and meet the criteria as below of the corresponding stages: * part a and pk expansion stage of part b: advanced malignant tumors; * cohort extension of part b: solid tumors such as locally advanced/metastatic breast cancer, relapsed/refractory ovarian cancer, locally advanced/metastatic liver cancer, etc; * part c and d: locally advanced/metastatic breast cancer with histological confirmation of er+, her2-; * 4. with at least one measurable lesion according to recist v1.1; * 5. eastern cooperative oncology group (ecog) performance status 0-1; * 6. life expectancy greater than 3 months; * 7. main organs meet the following criteria within 7 days before treatment: * hematology: no component blood transfusion, human granulocyte colony-stimulating factor (g-csf), and erythropoietin (epo) within 2 weeks prior to the investigational drug administration * absolute neutrophil count (anc) ≥1.5×10\^9/l; * platelet count (plt) ≥90×10\^9/l; * hemoglobin (hgb) ≥90 g/l or ≥5.6 mmol/l; * renal function: serum creatinine ≤ 1.5×uln or creatinine clearance rate ≥ 50 ml/min; * liver function: total bilirubin (tbil) ≤ 1.5×uln, or ≤ 3×uln for patients with gilbert syndrome; alanine aminotransferase (alt) and aspartate aminotransferase (ast)≤ 2.5×uln, or ≤ 5×uln in case of liver metastases; * coagulation function: activated partial thromboplastin time (aptt)≤ 2×uln; international normalized ratio (inr)≤ 2×uln; * 8. the serum pregnancy test for women of childbearing potential (wocbp) is negative within 7 days prior to the first dose of the investigational drug. patient and his/her spouse must agree to take adequate contraception from signing of icf to 6 months after the last dose, during which women should be non-lactating and men should refrain from donating sperms; * 9. patients voluntarily participate in this clinical study, understand the study procedures and sign the icf. exclusion criteria: * 1. have received anti-tumor treatments such as chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, etc. within 4 weeks before the first dose of the investigational drug; * 2. have received other unmarketed clinical investigational drugs or treatments within 4 weeks before the first dose of the investigational drug; * 3. have received major surgery (excluding needle biopsy), or severe unhealed wounds, trauma, etc. within 4 weeks before the first dose of the investigational drug in the study; * 4. have received glucocorticoids for systemic therapy over 7 days (prednisone\>10 mg/day or equivalent doses) or other immunosuppressant within 2 weeks before the first dose of investigational drug, and patients who need long-term use these therapies; * 5. have received potent inhibitors or inducers of cyp3a4 and inhibitors of p-gp within 1 weeks before the first dose of the investigational drug; * 6. the adverse events due to previous anti-tumor treatments without recovering to grade 1 (except for alopecia; some toxicities may be excluded as judged by the investigator) according to nci-ctcae v5.0; * 7. breast cancer patients with visceral crisis or symptomatic visceral metastasis; * 8. with active central nervous system (cns) metastasis and/or cancerous meningitis; * 9. active hbv or hcv infection (hbsag positive and/or hbcab positive with hbv dna ≥ 2000 iu/ml, and hcvab positive with hcv rna positive), or hiv positive; * 10. participants with a history of severe cardiovascular disease; * 11. inability to swallow medications orally, or conditions that, in the judgment of the investigator, significantly affect gastrointestinal absorption; * 12. patients who have received a live attenuated vaccine within 2 weeks before the first use of the investigational drug or plan to receive during the study; * 13. other situations that the investigator considers not suitable for participating in the clinical study.